The objectives of the proposed research are to determine: (1) the physiological mechanisms which regulate creatine biosynthesis during development of the mammalian fetus. In order to accomplish this objective we intend to identify the factors which promote the development of the enzyme which catalyzes the synthesis of creatine, namely, guanidinoacetate N-methyltransferase (GMT) in the fetal liver of the rat and guinea pig. Appropriate hormones such as thyroxine, glucagon, hydrocortisone and insulin as well as creatine precursors will be administered to intact fetuses in utero and after 12-24 hours the GMT activity of fetal liver will be assayed in order to determine if the hormonal stimulus can evoke the premature formation or accelerate the accumulation of the enzyme; (2) whether creatine can cross the placenta in the guinea pig and whether placental transport is an important source of creatine for the growing fetus. Our approach will be to administer creatine-1-C14 i.v. to the guinea pig by continuous infusion and then, after insuring that isotopic equilibration has been achieved, to determine the amount of radioactivity in the blood and several tissues of the mother and fetus; and (3) whether a known competitive inhibitor of creatine transport in skeletal muscle of the rat is an embryotoxic or teratogenic agent, and if it is, to determine whether its toxicity or teratogenicity is related in any way to interference with creatine metabolism or transport in the developing fetus.